Some of the cognitive abnormalities exhibited by schizophrenic patients suggest that the dorsolateral portions of the prefrontal cortex (DLPFC) are dysfunctional in this disorder. It also has been hypothesized that the dysfunctional of the DLPFC in schizophrenia may be related to abnormalities in the dopamine (DA) projection from the midbrain to this cortical region. To determine how disturbances of DA action may be involved in schizophrenia, it is essential to understand the role that DA plays in normal DLPFC function. The ultimate goal of this project is to elucidate the neurophysiological mechanisms by which DA affects activity in the monkey DLPFC. A central hypothesis that has been developed within the Center is that DA modulates the ability of excitatory synaptic inputs to initiate action potentials in neurons of the DLPFC. Although there is considerable evidence in favor of this hypothesis, the mechanisms underling DA modulation have not been elucidated. Recent advances in our understanding of synaptic integration suggest that DA could act by modulating the activity of postsynaptic voltage-dependent conductances that amplify distal excitatory synaptic inputs to DLPFC pyramidal cells. The research proposed in Project 5 will critically test this idea, determine the receptors and channels involved, and examine the implications of this mechanism of DA action for integration of synaptic signals. To achieve these goals, we will utilize the strengths we will utilize the strengths of two powerful experimental systems, the monkey in vitro brain slice and primary cultures of rat cortical cells. The specific aims of this project are to test the following two hypotheses: 1) DA modulates synaptic communication in the monkey DLPFC by regulation of voltage dependent conductances; and 2) DA modulates the activity of voltage-dependent Na+ and/or Ca2+ conductances of monkey PFC pyramidal cells.